The synthesis and screening of small molecule combinatorial libraries is an important tool in drug discovery. A convenient format for the generation of these libraries is the preparation of compounds on a solid support Solid-phase organic synthesis (SPOS) is especially useful for many synthetic transformations, since reagents can be used in large excess to drive reactions to completion, and any unreacted amount of reagents and soluble byproducts can be easily removed by filtration (see Thompson and Ellman 1996, Chem. Rev. 96:555.; Herkens et al. 1996, Tetrahedron 52:4527; Fruchtel and Jung 1996, Angew. Chem. Int. Ed. Engl. 35:17-42; Balkenhold et al. 1996, Angew. Chem. Int Ed Engl. 35:2288-2337).
Substituted heterocyclic compounds offer a high degree of molecular diversity and have proven to be broadly useful as therapeutic agents. The benzimidazole, benzoxazole, and benzothiazole ring systems, in particular, are present in many known herbicides, fungicides, and drugs used in human as well as veterinary medicine. The generic structure and numbering system of these compounds are shown below. ##STR1##
Benzimidazoles, benzoxazoles, and benzothiazoles have been shown to exhibit antiviral (Salluja et al. 1996, J. Med. Chem. 39:881-891), antiulcer (Cereda et al. 1987, Eur. J. Med. Chem. 22:527-537; Kugishima et al. 1994, Heterocyclic Chem. 31:1557-1559.), antihistaminic (Jerchee et al. 1952, Liebigs Annalen der Chemie 575:173; Janssens at al. 1981, Chem. Abstr. 94:30579), analgesic (Hunger at al. 1957, Experientia 13:400), antihelmintic (Gyurik et al. 1981, U.S. Pat. No. 4,258,198; 1981, Chem Abstr. 95:7284), antibacterial (Kusumi et al. 1988, J. Am. Chem. Soc. 110:2954; Suto et al. 1995, Tetrahedron Lett. 36:7213; Chaney et al. 1974, J. Am. Chem. Soc. 96:1932; David et al. 1982, J. Antibiotic. 35:1409; Westly et al. 1983, J. Antibiotic. 36:1275), antiparasitic (Haugwitz et al. 1979, J. Med. Chem. 22:1113; Haugwitz et al. 1982, J. Med. Chem. 25:969), and antiinflammatory properties (Dunwell et al. 1975, J. Med. Chem. 18:53; Dunwell et al. 1975, J. Med. Chem. 18:1158; Evans et al. 1977, J. Med. Chem. 20:169; Dunwell et al. 1977, J. Med. Chem. 20:797), or other biologically relevant actions such as inhibition of elastase (Edwards et al. 1992, J. Am. Chem. Soc. 114:1854; Edwards et al. 1995, J. Med. Chem. 38:87; Edward et al. 1995, J. Med. Chem. 38:3972), and H.sub.2 -antagonist properties (Katsura et al. 1992, Chem. Pharm. Bull. 40:371; Katsura et al. 1992, Chem. Pharm. Bull. 40:1424).
In spite of their importance as phannacophoric scaffolds, there has been a lack of mild and efficient techniques for synthesizing benzimidazoles, benzoxazoles, and benzothiazoles on a solid support and, particularly, for producing libraries of derivatives for biological screening. Thus, the development of strategies for the solid phase synthesis of these heterocyclic systems and derivatives thereof is not only highly desirable, but also economically advantageous (see Nefzi et al. 1997, Chem. Rev. 97:449-472).
Benzimidazoles, benzoxazoles, and benzothiazoles are usually prepared in solution by heating a 1,2-arylenediamine, 2-aminophenol, or 2-aminothiophenol with carboxylic acids or their derivatives (chlorides, anhydrides, esters, amides, imino esters) at elevated temperatures and/or in the presence of strong acids (see Preston, P. N. Benzimidazoles and Congeneric Tricyclic Compounds. In Heterocyclic Compounds; Preston, P. N., Ed.; John Wiley & Sons, NY, 1981, Vol. 40, pp 6-60). These conditions, however, are not always suitable for solid phase organic synthesis, particularly when thermally sensitive polymeric supports and/or acid-labile linkers are employed. In spite of this fact, the current methods for the solid phase synthesis of benzimidazoles and benzoxazoles are for the most part based on the above general approach and, therefore, subjected to its limitations. For example, Phillips and Wei (Tetrahedron Lett. 37 (1996) pp.4887-4890) disclose a process for the solid phase synthesis of benzimidazoles that includes heating an immobilized 1,2-arylenediamine with an imino ester. Although the use of an imino ester allows one to carry out the reaction under essentially neutral conditions, a large excess of the reagent (ca. 30 eq.) and prolonged heating (ca. 55-90.degree. C. for 24-40 h) are still needed to induce heterocycle ring formation. Imino esters, on the other hand, are not readily available reagents and must be individually prepared, isolated, and purified by conventional methods before they can be used in the synthesis of combinatorial libraries.
Wang and Hauske (Tetrahedron Lett. 38 (1997) pp.6529-6532) disclose a method for the solid phase synthesis of benzoxazoles that involves a two-step reaction, in which a carboxylic acid is first amidated with a 2-aminophenol, and the resulting amidophenol is then cyclized intramolecularly. This method relies on the selective amidation of the resin-bound carboxylic acid with a 2-aminophenol without concomitant esterification, and in the intramolecular nature of the process.
Benzimidazoles have also been obtained in solution by treatment of a 1,2-arylenediamine with aldehydes and an oxidizing agent (see Chikashita et al. 1987, Bull. Chem. Soc. Jpn. 60:737-746; Yadagiri and Lown 1990, Synth. Commun. 20:955-963; Patzold et al. 1992, Synth. Commun. 22:281-288; Vanden Eynde et al. 1995, Tetrahedron 51:5813-5818), or by treatment of a 1,2 arylenediamine with cyanogen bromide (see Rastogi and Sharma 1983, Synthesis 861-882). Although not as widely publicized as the thermal cyclization of 1,2-arylenediamines with carboxylic acids or their derivatives, these alternative methods are known to afford benzimidazoles under very mild conditions.
A few of these methods have been applied to the solid phase synthesis of benzimidazoles from either immobilized aldehydes (see Sun et al. 1998, Bioorg. Med. Chem. Lett. 8:361-364) or immobilized 1,2-arylenediamines (see Mayer et al. 1998, Tetrahedron Left. 39:6655-6658), but not both. In the first case, the oxidizing agent used is nitrobenzene and the reaction is still performed at high temperature (ca. 130.degree. C.); in the second case, the oxidizing agent is DDQ and the reaction is carried out at or near room temperature.